Macromolecular architecture has been recognized as an important tool to obtain polymers with tailored properties. Materials exhibiting a distinct relationship between molecular architecture and macroscopic properties include dendrimers and hyperbranched polymers and it is known that introducing branching units into linear polymers can dramatically change their physical properties. Dendrimers and hyperbranched polymers possess unique three-dimensional chemical structures and have many potential applications in such things as coatings, additives, catalysts, drug delivery systems, and bioimaging systems. Unlike linear polymers, dendrimers and hyperbranched polymers exhibit unique properties including non/low chain entanglements, low viscosity, high solubility, unusual self-assembly behaviors, a large number of terminal groups that can be chemically modified, and a large capacity of encapsulation for guest molecules. Despite the well-defined monodisperse architecture of dendrimers, scalability challenges have limited their widespread clinical and commercial applications. In contrast, hyperbranched polymers can be conveniently synthesized on a large scale in one-pot reactions using step growth or ring opening polymerization and require little or no additional purification. Hyperbranched polymers not only retain some of the structural features and properties of dendrimers, they are more commercially accessible.
Efforts have been made to diversify the pool of synthetic polymers to find those that meet design criteria for more advanced applications. Hyperbranched polymers, especially synthetic biodegradable hyperbranched polymers, have been receiving more and more attention in materials science as well as in biomedical science, and include hyperbranched polyethers, polyesters, polyphosphates, and polysaccharides. Over the last fifteen years or so, for example, synthesis of hyperbranched aliphatic polyethers, (poly(3-ethyl-3-oxetanemethanol)) by a cationic ring-opening polymerization; a hyperbranched polyglycerol obtained by anionic ring opening multi-branching polymerization; synthesis of potentially biodegradable homo- and co-polyesters of gallic acid, phloretic acid and vanillic acid; synthesis of hyperbranched poly(ester amide)s via direct polycondensation from commercially available aliphatic carboxylic anhydrides and multihydroxyl primary amines; and synthesis of hyperbranched polyphosphates using self-condensing ring opening polymerization of cyclic phosphate monomers 2-(2-hydroxyethoxy)ethoxy-2-oxo-1,3,2-dioxaphospholane without catalyst, have all been reported. All of these hyperbranched polymers have shown potential for the self-assembly of micelles and biomedical applications.
α-Amino acid-based poly(ester urea)s have proven to be important materials for biomedical applications because of their excellent blood, tissue compatibility and non-toxic hydrolysis byproducts. Their semi-crystalline structure provides a non-chemical method to enhance their mechanical properties and processing characteristics. Also, their synthetic flexibility yields a diverse physical and chemical landscape that is available for exploration. The synthesis of a 1,6-hexanediol L-phenylalanine-based PEU, poly(1-PHE-6) that possesses an elastic modulus (6.1 GPa) nearly double that of poly(lactic acid) (2.9 GPa) and when crosslinked with osteogenic growth peptide maintains potent osteoinductive activity, has been previously demonstrated. See, e.g., Kasuga, T.; Ota, Y.; Nogami, M.; Abe, Y. Biomaterials 2000, 22, 19 and Stakleff, K. S.; Lin, F.; Smith Callahan, L. A.; Wade, M. B.; Esterle, A.; Miller, J.; Graham, M.; Becker, M. L. Acta Biomaterialia 2013, 9, 5132, the disclosure of which are encorporated herein by reference in their entirety. Significantly, there has been no evidence of inflammation due to degradation related acidification when poly(l-PHE-6) has been implanted in vivo. A series of linear L-phenylalanine-based PEU that possess variations in diol chain length that result in tunable mechanical properties, thermal characteristics and degradation rates have also been developed. See, e.g., Yu, J.; Lin, F.; Lin, P.; Gao, Y.; Becker, M. L. Macromolecules 2014, 47, 121, the disclosure of which is encorporated herein by reference in its entirety. The mechanical data span a range of values that overlaps with several currently clinically available degradable polymers and the materials exhibited a diol length dependent degradation process that is tunable. In addition, the synthesis of PEU nanofibers carrying pendent “clickable” groups including alkyne, azide, alkene, tyrosine-phenol and ketone groups on modified tyrosine amino acids have been reported. See, e.g., Lin, F.; Yu, J.; Tang, W.; Zheng, J.; Xie, S.; Becker, M. L. Macromolecules 2013, 46, 9515, the disclosure of which is encorporated herein by reference in its entirety.
It has been found, however, that these PEU polymers lacked the stability necessary for sterilization, limiting their use for use in vivo for regenerative medicine and/or drug delivery. What is needed in the art is a degradable amino-acid-based PEU polymer for use in regenerative medicine and/or drug delivery applications has tunable mechanical and thermal properties, but is sufficiently stable to permit such things as ethyloxide (ETO) sterilization without degradation and/or significant loss of function.